We also highlight CD44 interaction with many components in the tumour microenvironment and its functional roles and involvements in tumour progression and aggressiveness, as well as its clinical relevance and the possibility of targeting CD44 for cancer therapy. This review summarises current insights on CD44 structure and isoforms as well as the CD44-mediated oncogenic signalling pathway in several cancers. Increasing evidence suggests that some CD44 isoforms are promising prognostic biomarkers and therapeutic targets for many cancers. Thus, a significant area of study is aims to further define the functional roles of the different CD44 isoforms in various types of cancers. Although abundant progress has been made regarding the structure and functional roles of CD44 and its diverse isoforms, the expression level associated with poorer clinicopathological impacts remains unknown. In addition to its role in cellular adhesion and communication, it is essentially involved in several biological and functional processes, such as lymphopoiesis and myelopoiesis, leukocyte activation, angiogenesis and the release of cytokines, as well as many pathological processes including metastasis, epithelial–mesenchymal transition (EMT), cellular growth, proliferation, migration and invasion. It is a member of the cell adhesion molecules (CAMs) family that plays important roles in cellular communication and adhesion between cells and the ECM. Currently, CD44 is recognised as the main cell surface receptor for hyaluronate, which is the major extracellular matrix (ECM) component. It is a single polypeptide chain encoded by a conserved gene located on either human chromosome 11 or murine chromosome 2 and is also known as In (Lu)-related protein p80, Pgp-1/Ly-24, ECMRIII, HUTCH-1, Hermes antigen, and importantly, hyaluronate receptor. Subsequently, it was cloned and classified as a cartilage link protein family member. In the early 1980s, CD44 was first identified as a glycoprotein expressed on human and murine mesenchymal cells. As a non-kinase cell surface transmembrane glycoprotein that is overexpressed in CSCs and frequently undergoes alternative splicing to support cancer progression, it could severely influence treatment outcomes. Numerous investigations support the role of cancer stem cells (CSCs) and their associated markers in tumour malignancies, for example, the cluster of differentiation 44 or CD44. The clinical significance and prognostic value of CD44 and the potential of CD44 as a therapeutic target in cancer are also addressed.Ĭancer manifests as uncontrolled cell proliferation, followed by enhanced migration, invasion, and metastasis to other parts of the body. This review summarises current research regarding the different CD44 isoform structures and their roles and functions in supporting tumourigenesis and discusses CD44 expression regulation, CD44-signalling pathways and interactions involved in cancer development. Nonetheless, high CD44 expression significantly contributes to enhanced tumourigenic mechanisms, such as cell proliferation, metastasis, invasion, migration and stemness hence, CD44 is an important clinical target. However, there are contradictory results regarding whether high or low CD44 expression is associated with worsening clinicopathological features, such as a higher tumour histological grade, advanced tumour stage and poorer survival rates. The interaction of such isoforms with ligands, particularly hyaluronic acid (HA), osteopontin (OPN) and matrix metalloproteinases (MMPs), drive numerous cancer-associated signalling. The CD44 gene regularly undergoes alternative splicing, resulting in the standard (CD44s) and variant (CD44v) isoforms. Cells overexpressing CD44 possess several CSC traits, such as self-renewal and epithelial-mesenchymal transition (EMT) capability, as well as a resistance to chemo- and radiotherapy. CD44, a non-kinase cell surface transmembrane glycoprotein, has been widely implicated as a cancer stem cell (CSC) marker in several cancers.
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